Our long term goal is to elucidate the immunologic and genetic basis of alopecia areata (AA). Towards this end, we have recently developed a mouse model of the human disease. The exciting results of our initial experiments indicate that these mice have spontaneous hair loss that clinically resembles that of the human disease, and abnormal autoantibodies to hair follicles (HF), which again, are similar to those present in human AA. A strong collaboration has been forged between The Jackson Laboratory, where the mouse model was developed, and the NYU laboratory, where the immunological abnormalities were discovered. The specific goals of this joint proposal are to study (1) the role of HF autoantibodies in the pathogenesis of AA. This will involve: a) confirming that abnormal autoantibodies to HF are specifically associated with C3H/HeJ mice with AA; b) determining whether the presence of these antibodies precedes or follows the development of hair loss and whether these antibodies can induce alopecia when administered to unaffected animals; and c) characterizing the individual antigens defined by abnormal HF antibodies present in C3H/HeJ mice with alopecia, their relation to HF antigens implicated in the pathogenesis of AA in humans, and whether the expression of these antigens is genetically determined. (2) The genetic basis of murine AA. The AA phenotype in mice has an autosomal dominant pattern of inheritance with poor penetrance, as do some forms of human AA. An intercross and backcross strategy with C57BL/6J mice has identified putative linkage for the AA susceptibility locus. This approach will be repeated using an intersubspecific cross with Mus musculus castaneus (CAST/Ei) to generate a high resolution map. Using the Mouse Genome Database (MGD), candidate genes will be identified and investigated. Successful completion of this grant will further our understanding of the causes of AA and hopefully lead to an improved treatment for this common and disfiguring disease.